Abstract SKN-1/NRF2 is a conserved cytoprotective transcription factor that plays established dose dependent roles in response to diverse cytotoxic stressors. As such, the degree of SKN-1/NRF2 activity can impact survival and physiological responses to environmental toxins. Although it makes sense that increased SKN-1/NRF2 activity could be protective, it remains possible that the NRF2 response itself contributes to disease pathology. As such, a major question is whether SKN-1/NRF2 activation is universally helpful or if it can also drive pleiotropic consequences over the lifespan. We have uncovered the existence of a conserved signature, defined by metabolic dysregulation, in worms and mice with activated SKN-1/NRF2. These metabolic defects mask the potentially positive cytoprotective effects of SKN-1/NRF2 activation later in life. The central hypothesis driving our proposal is that animals with activated SKN-1/NRF2, have enhanced resistance to stress, but also increased incidence of metabolic disorders that compromise health later in life; this ultimately diminishes life expectancy. To test our hypotheses, we propose two interconnected specific aims. In Aim 1, we will biochemically define the age-related depletion of somatic lipids when SKN-1/NRF2 is activated, which ultimately leads to reduced health later in life. We will also examine the lifespan and healthspan of animals that where the somatic lipid depletion phenotype is suppressed, by genetic or nutritional interventions, while SKN-1/NRF2 activation is maintained. This will functionally uncouple the positive and negative effects of SKN-1/NRF2 activation on healthspan and lifespan. In Aim 2, we will define the mechanisms underlying the metabolic and stress resistance phenotypes resulting from activated SKN-1/NRF2 by elucidating the molecular, and spatial determinants of these responses, whose capacity is governed by age. Finally, in Aim 3, we will define a new mechanistic link between lipid metabolism and immune activation that is governed by activated SKN-1/NRF. The successful completion of the proposed research will inform strategies to capitalize on the health promoting benefits of molecules like SKN-1 and NRF2 while avoiding pleiotropic outcomes over the lifespan.